Targeting gut-brain axis to eliminate CNS reservoirs

University Of Nebraska Medical Center, Omaha NE

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Abstract

The gut and brain are connected via the gut-brain axis (GBA), wherein the neural and immunological signals are transmitted between the central nervous system (CNS) and the gut. During acute infection, HIV/SIV targets gut CD4+ T cells and macrophages because these sites express high numbers CCR5-expressing activated CD4+ T cells. Targeting of the gut during HIV/SIV infection results in severe depletion of gut CD4+ T cells and ensuing mucosal tissue dysfunction resulting in leaky gut, microbial translocation and chronic immune activation. The integrin ?4?7 is found at high levels on the surface of some CD4+ T cells and is involved in gut- cell trafficking. Some strains of HIV/SIV are able to bind to ?4?7 on ?4?7hi CD4+ T cells making the cells more susceptible to infection. Increased frequency of ?4?7hi-expressing CD4+ T cells within the gastrointestinal associated lymphoid tissues (GALT) at the time of infection appears to correlate with increased viral loads and enhanced rate of disease progression. Intravenous (i.v.) administration of anti-?4?7 monoclonal antibody to rhesus macaques protected the GALT from infection when RMs were challenged with either i.v, i.r or IVAG routes. The protection was established by both enhancing the levels of peripheral blood naive, central memory CD4+ T cells. Remarkably, administration of anti-?4?7 mAb to ART-treated SIV-infected RMs resulted in a highly significant, unprecedented suppression of plasma/GALT viral loads even after ART treatment interruption. These studies, taken together, highlight the role of ?4?7 in HIV pathogenesis and treatment. Since the gut and brain are connected via the GBA, we hypothesize that controlling viral loads in the GALT will lead to diminished viral reservoirs in gastrointestinal tissues, which indirectly reduces the CNS viral reservoir. To test this hypothesis, groups of macaques will be administrated anti-?4?7 antibody during acute infection along with combination anti-retroviral therapy ART (cART). The viral loads from plasma, CSF and CNS tissue (at necropsy) will be assessed including the measurement of phenotypic characteristics of immune cells and inflammatory markers (Aim 1). Furthermore, sensitive reservoir assays such as viral outgrowth assay (VOA) and highly sensitive Tat/rev Induced Limiting Dilution Assay (TILDA) will be used to measure inducible virus in macrophages/microglia (Aim 2) purified from the brains of the animals in Aim 1, which will identify the establishment of the viral reservoir in the CNS.